The possibility of gene therapy to treat cardiac chronotropic incompetence took a step forward with the successful, if transient, enhancement of heart rate in a large animal model by human gene transfer.

Having already established the principle in a mouse model, with transfer of constructs encoding the β₂ human adrenergic receptor resulting in enhanced heart rate, Edelberg and colleagues repeated the process in a Yorkshire pig model — chosen for its similarity to the human cardiovascular system. Plasmids encoding either human β₂ adrenergic receptor (pBR322-β actin promoter-β₂ adrenergic receptor) or control constructs (pBR322-β actin promoter-β galactosidase) and a co-injection vector (plasmid construct encoding humanised green fluorescent protein with a cytomegalovirus promoter) were injected by cardiac catheterisation into the right atrial myocardium (six pigs for β₂ adrenergic receptor and five for controls) in a randomised double blind procedure.

Two days later the average heart rate before injection (108 (SD 16) beats/min) was significantly increased in pigs receiving the β₂ adrenergic receptor construct (163 (33) beats/min; p<0.05 compared with preinjection) compared with those receiving control constructs (127(25) beats/min; p>0.3 compared with preinjection). The increase before and after injection was almost a 50% increase in heart rate (p<0.01 compared with that for the controls). After sacrifice sections of the injection sites of the excised hearts were stained with immunofluorescent stain specific for the human β₂ adrenergic receptor. Dual fluorescence microscopy showed specific staining only in those hearts injected with the β₂ adrenergic receptor construct, indicating expression of the encoded genes.